TGF-[unreadable] plays a central role in bone metastases. lt is released in high concentrations from bone during osteoclastic bone resorption, a process that is active in all bone metastases. TGF-[unreadable] enhances tumor factors that increase osteolytic bone destruction. The actions of TGF-[unreadable] on osteoblasts &osteoclasts &consequent contributions to tumor growth in bone are less well characterized. We hypothesize that, in addition to its effects on tumor cells, TGF-[unreadable] acts on osteoblasts to regulate factors, such as Wnt ligands and BMP antagonists, which have differing effects on the growth of osteolytic vs. osteoblastic tumor types. In addition, TGF-[unreadable] activates osteoclasts to increase bone resorption in all types of skeletal metastases. Dr. Neil Bhowmick, Vanderbilt University Tumor Microenvironment Network (VUTMEN), &Dr. Theresa Guise, Indiana University, will study the role of TGF-[unreadable] signaling in osteoblasts &osteoclasts in the bone microenvironment and the effect on bone metastases. The PIs will test: Hypothesis 1: TGF-[unreadable] signaling in osteoblasts regulates tumor growth in bone, &the responses are dependent on whether the tumor is predominantly osteolytic or osteoblastic. Aim 1.Determine the role of osteoblastic responsiveness to TGF-[unreadable] in the establishment and progression of bone metastases of all types: Mice with osteoblasts-targeted deletion or activation of TGF-[unreadable] signaling will be generated &the effect on bone metastases by osteolytic, osteoblastic or mixed tumors of breast, prostate, &melanoma will be studied. Hypothesis 2: TGF-[unreadable] signaling in osteoclasts increases bone resorption, favoring tumor growth in bone, independent of the type of bone metastasis. Aim 2. Determine the role of osteoclastic responsiveness to TGF-[unreadable] in the establishment and progression of all types of bone metastases. Mice with osteoclast targeted deletion or activation of TGF-[unreadable] signaling will be generated &the effect on bone metastases will be studied as in Aim 1. Hypothesis 3: Osteoblasts respond to TGF-[unreadable] via secretion of factors, in a Stat3-dependent manner, to alter tumor behavior in bone. Aim 3. Identify mechanisms of TGF-[unreadable]-mediated paracrine regulation of metastatic tumor growth in bone: the role of Stat3 regulation of wnt5a and chordin will be studied in mouse models and human tissue.